ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12533A>G (p.Asn4178Ser) (rs794728787)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182820 SCV000235206 likely pathogenic not provided 2016-09-01 criteria provided, single submitter clinical testing The N4178S likely pathogenic variant in the RYR2 gene was reported as a novel mutation" in three of 155 unrelated probands with either a confirmed clinical diagnosis of CPVT or an initial diagnosis of exercise-induced LQTS but with QTc <480 ms and subsequent negative LQTS genetic testing; specific clinical information for affected probands was not provided (Medeiros-Domingo et al., 2009). Subsequently, N4178S was identified in a Japanese individual with CPVT and was absent from both clinically-unaffected parents (Kawamura et al., 2013; Ohno et al., 2015). In addition, the N4178S variant has been identified independently in two other individuals referred for CPVT testing for at GeneDx; familial segregation data available for one of these individuals was consistent with de novo inheritance. Moreover, N4178S was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N4178S variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the N4178S variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Finally, a missense variant at the same residue (N4178Y) has been reported in the Human Gene Mutation Database in association with CPVT (Stenson et al., 2014); however, the pathogenicity of this variant has not been definitely determined.Therefore, this variant is likely pathogenic."
Invitae RCV001242098 SCV001415164 likely pathogenic Catecholaminergic polymorphic ventricular tachycardia 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 4178 of the RYR2 protein (p.Asn4178Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, 26114861). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 201334). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Asn4178 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been observed in individuals with RYR2-related conditions (PMID: 19398665), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues RCV001248790 SCV001422300 pathogenic Catecholaminergic polymorphic ventricular tachycardia type 1 2020-01-31 criteria provided, single submitter clinical testing

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